Lung cancer is a multifactorial disease. Hereditary, genetic, and environmental factors interact in its genesis. The principal risk factor for lung cancer is smoking. However, the workplace provides an environment in which there is a risk of exposure to carcinogens. The International Agency for Research on Cancer currently lists 19 substances/work situations/occupations that have been proven to be associated with lung cancer (group 1). Thorough occupational history taking is not widely practiced in patients with lung cancer, which has a negative impact on the investigation of causality and, consequently, on the identification of cases of occupational cancer. The objectives of this review were to list the agents that are recognized as causes of lung cancer, to discuss the contribution of occupation to the development of the disease, to cite national studies on the subject, and to propose a list of procedures that are essential to the appropriate investigation of causality between lung cancer and occupation.

Carcinogens are often found in the workplace. Until the 1970s, most of the known human carcinogens were encountered in the workplace. The work environment remains a significant source of carcinogens.(1)

Carcinogenesis is a multifactorial process in which there is interaction among hereditary, genetic, and environmental factors that lead to uncontrolled cell growth. From this standpoint, occupational cancer is not considered a typical occupational disease, but rather a disease in which work, as an environmental factor, plays a decisive pathogenic role, by Schilling's criteria, which will be discussed below.(2)

The principal risk factor for lung cancer is smoking, which is largely responsible for the development of the disease in men and women. It is estimated that 10-15% of all deaths from lung cancer in the USA are caused by risk factors other than smoking. In isolation, these would account for 16,000-24,000 deaths per year, which would still place lung cancer among the ten most deadly forms of cancer.(3) Occupational carcinogens can act alone or in synergy with smoking. A review of lung cancer in Brazil discussed the principal risk factors, notably smoking, and the economic sectors where carcinogens are strongly present. The economic sectors listed included mining, mineral processing, metal processing, the chemical industry, and the construction industry, including the manufacture of building materials.(4)

Studies on the relationship between lung cancer and occupation, regardless of the type, depend on thorough occupational history taking and on the proper classification of cases and controls (when applicable) within exposure groups. Typically, exposure is divided into the so-called lists A and B.(5) List A comprises the types of occupations and industries that have been classified as being definitely associated with lung cancer, whereas list B involves the types of occupations and industries that are suspected of being associated with this form of cancer. Lung cancer, leukemia, and mesothelioma account for most forms of occupational cancer.(6) Exposure to asbestos, alone, is estimated to be responsible for at least half of the cases of lung cancer attributable to occupation.(7,8)

Recently, the Brazilian National Ministry of Health issued a decree making it mandatory that cases of occupational lung cancer be reported.(9) The Social Security Regulation-Decree 3048/99, amended by Decree no. 6,957 of September 9, 2009-presents a list of work-related cancers, among which is occupational lung cancer, that are recognized for disability payment purposes.(10) Due to the importance of the subject, as well as to the fact that thorough occupational history taking is not widely practiced in patients with lung cancer and that the subject is infrequently addressed in the Brazilian literature, it is relevant that the matter be discussed by specialists who deal with respiratory diseases in their routine. The objective of this review was to provide pulmonologists with information that will contribute to a more thorough investigation of the etiology of cases of lung cancer, furthering the understanding of the epidemiology of the disease in Brazil.

Classification of carcinogenic agents

The International Agency for Research on Cancer (IARC) was established in 1965 as a member institution of the World Health Organization. For more than 30 years, the IARC has produced publications on carcinogenic agents, and such publications have evolved into a program of monographs.(11,12)

The term "agent" refers to chemicals (substances, compounds, elements), groups of chemicals, complex mixtures, environmental or occupational exposure, behavioral or cultural aspects, biological agents, and physical agents. Therefore, "agents" refer to substances, occupations, or situations that affect cancer risk. This term will be used throughout the text.

Each section has specific guidelines and methods to be analyzed. For instance, the evaluation of studies of cancer in humans includes epidemiological cohort studies, epidemiological case-control studies, ecological studies, and intervention studies. Occasionally, studies of biological markers are included. Studies are considered based on their quality, on the existence of temporal relationships between exposure and effects and on causality criteria. Meta-analyses and combined analyses are also admitted. In the final evaluation, the agent is classified, in accordance with the sections above, as belonging to one of four groups (Chart 1).

Occupational agents related to lung cancer

Always using the reputable reference of the IARC, with its criteria and classifications, we present a list of agents that are undoubtedly carcinogenic to humans-classified as Group 1.(13)

This classification is routinely reviewed, and, according to its last update (16/01/2009), Group 1 comprises 108 items, among which there are pure substances, mixtures, exposure circumstances (several of which are occupational), and habits. Although the classification does not specify the form of cancer caused, this can be found in the IARC monographs,(14) which indicate that lung cancer is one of the major forms of cancer on the list.

The IARC studies show that lung cancer, in addition to its various occupation-related causes, is related to habits, such as smoking, or to exposure circumstances, such as emissions from domestic coal burning. There are 20 agents among the substances, mixtures, or occupations related to lung cancer. In addition, there are several other agents listed in Group 2A, that is, agents that are probably carcinogenic to humans, and many of them might be included in Group 1 in the coming years. The present review article will address only the agents classified as Group 1, a group that leaves no room for speculation, and related to lung cancer, thereby making it possible to establish a more objective relationship between the disease and the agent. Chart 2 lists the 20 agents mentioned.

In order to facilitate the task of obtaining information on carcinogenic agents with which a patient might have had contact, a list of some activities and occupations that are common in Brazil and can involve exposure to agents classified as IARC Group 1 (Chart 3) was drawn up, in addition to the occupations, per se, classified as carcinogenic to the lung (Chart 2).

Occupational burden of lung cancer

The occupational risks of lung cancer are quantitatively estimated by calculating the Population Attributable Risk (PAR). The PAR measures the burden of disease attributable to a given risk and estimates its confidence interval.(15) The methods for calculating the PAR depend on knowing the proportion of the population exposed to the risk.

The PAR is calculated based on risk measures (relative risk or odds ratio). Since the occupational risks of lung cancer vary according to the socioeconomic profile of the population, it is admissible that the calculation varies in studies conducted in different regions. One group of authors, using a mean PAR of 9%, estimated that, in 2000, there were 102,000 deaths from occupational lung cancer worldwide.(6) In two recent studies, the PAR was calculated to be 11.6% and 4.9%, respectively.(8,16)
In an estimate made in the USA and derived from relative risks described in the literature, PAR was calculated to be 9%.(7) Although the fraction of workers exposed to occupational carcinogens in developing countries might be similar to that found in developed countries, it should be borne in mind that the exposure conditions are much worse in the former.

The significance of the exposure to occupational carcinogens also varies according to smoking status. A multicenter case-control study conducted in Europe concluded that the odds ratio for lung cancer in nonsmoking females was 1.75 (range: 0.63-4.85), although no increased risk was detected for males.(17) Another cohort study did not detect excess risk in nonsmoking females exposed to agents on list A or B, except in specific situations for some groups of occupations or industries that presented excess risk (painting activities, the rubber industry, the footwear industry, the wood industry, and the paper industry).(18)

Occupational exposure to welding fumes and dusts was associated with a higher relative risk of epidermoid carcinomas than that of other histological types.(19) In one study, there was excess risk of small cell carcinoma and epidermoid carcinoma in comparison with that of adenocarcinoma.(16)
Therefore, it is possible that there is an association between a given type of exposure and certain cell types of lung cancer.

Despite the knowledge that has been accumulated for decades,
establishing occupational causality in cases of cancer remains extremely uncommon. In a study conducted in Great Britain, it was calculated that, in 2004, approximately 7,300 deaths would be attributable to cases of occupational cancer, in contrast with the statistical records of 223 deaths from occupational diseases in the same year.(8)

In Brazil, data on cancer and occupation are scarce. One study involving 316 cases and 536 controls at 14 hospitals in the city of São Paulo, Brazil, calculated that the risk of cancer doubled (OR = 1.97; 95% CI: 1.52-2.55) when groups at higher and lower risk of exposure to carcinogens were compared.(20) These results were similar to those reported in a large population-based study conducted in Denmark, in which the risk of lung cancer in workers with technical-level training was found to be twice that observed in workers with a college education.(21) A second case-control study of occupational risks and lung cancer revealed a significantly increased risk for workers engaged in the production of industrial machinery, workers in the ceramics industry, and workers in the textile industry, the last ones being at excess risk only after performing the activity for more than 10 years.(22) Two case-control studies involving 1,793 and 1,004 cases of lung cancer and conducted in the USA and Germany, respectively, revealed a significantly increased risk of lung cancer in workers engaged in the production of sheet metal, workers in the metallurgical industry, and workers engaged in the production and installation of industrial machinery, as well as in workers engaged in other occupations.(23,24) We emphasize that published studies can be compared only if the number of cases involved is representative, detailed occupational data has been collected, and a similar classification of occupations has been used. Cases of lung cancer associated with exposure to asbestos and silica have been reported in the Brazilian literature.(25,26)

Due to the multifactorial character of cancer, it is complicated to estimate the disease burden attributable to risk factors. Although the contribution of occupational exposure is small, in comparison with that of smoking, it is much superior to that of other risks associated with lung cancer.(27)
Based on the evolution of the literature in recent decades, it is absolutely clear that environmental factors, together with increased life expectancy, have contributed to the higher rates of cancer in the population.(28)

How is a nexus established? Information gathering and a
practical guide to history taking

The approach to the relationship between occupation and lung cancer is complicated by two factors. First, the latency period (the time elapsed between the initiation of exposure and the recognition of the disease) is long. That results in what is known as recall bias, which occurs due to the long latency period between exposure and diagnosis. Second, there are confounding factors, notably smoking.

In Brazil, the social security system adopts Schilling's classification for the recognition of occupational diseases.(29) This classification divides the "strength" of the relationship between exposure and disease into three levels (groups)(2):

The group designated Schilling I comprises diagnosed diseases that are directly and almost exclusively related to occupational exposure, such as silicosis and lead poisoning. These are the classical occupational diseases.
The group designated Schilling II includes diseases that can be found in the entire population, but to which work was a contributing factor in those cases. Some examples are work-related musculoskeletal diseases (repetitive strain injuries or others) and coronary diseases, in which stress plays an important role. Work-related cancer is included in this group, since tumors of occupational origin might have causes other than those of the same tumors when non-work-related.
The group designated Schilling III includes diseases in which work triggers a latent disorder or aggravates a previously established disease. Allergic contact dermatitis, asthma, and mental disorders, for example, fit into this group.

In practice, the relationship between work and many of the diseases in the Schilling III group can be definitively confirmed or ruled out, such as in cases of allergic dermatitis after contact tests, or even in cases of asthma after specific bronchial provocation tests, or when peak flow curves are obtained in periods of work and of leave from work. However, the same is not true for the diseases in the Schilling II group, in which cases there is always room for doubt, even when the investigation is thorough.

Lung cancer is not always etiologically related to occupational exposure. Therefore, occupational history taking can be conducted at two levels of depth: a general inquiry, that is, a type of basic screening for occupations and substances; and a detailing of the history, after the detection of something suspicious in the initial screening.(30-33)

Pulmonologists can easily perform the general enquiry, but it should be borne in mind that they might need aid in detailing the history, since it is not possible for a single professional to retain and understand all of the information related to the complex world of work. If no occupational suspicion is raised in the initial approach, a more in-depth investigation will not be conducted. It is understood, therefore, that the basic occupational history plays a fundamental role in routine history taking.

All routine occupational history taking should include the initial and brief but no less comprehensive overview inquiry of present occupations, previous occupations, and specific types of exposure recognized as posing the greatest occupational risk for lung cancer, such as that to fumes, gases, dusts, and other aerosols (see Chart 4 for a suggestion of a guide).

After the first voluntary statement, there should be specific inquiries, preferably using a standard list of agents and types of exposure recognized as causing lung cancer (Charts 2 and 3). If the screening does not indicate occupations or environments with suspected agents, further history taking can be dispensed with.

When the etiology is hypothesized to be occupational and a suspected exposure is identified in the screening, the workplaces where the patients have been employed and the occupations they have had in their professional life should be detailed.(32) To that end, an appropriate amount of time should be allocated in the medical appointment. It is not possible to obtain quality information in a hasty manner. This detailing should follow a script covering from first to current job, preferably using a standard pre-approved data collection worksheet (Chart 5). This step should include the following:

Some occupations, such as that of welder, foundry caster, part trimmer, toolmaker, tool sharpener, emery grinder, jackhammer operator, crusher operator, enameller, etc, are difficult to understand for pulmonologists who have never witnessed these activities. The nomenclature used by the patients to designate their occupations should be faithfully recorded and should not deter physicians from searching for more detailed explanations about what these designations mean in practice. In the absence of visits to the workplaces, other sources of information should be consulted (Chart 6).

A common situation that merits attention is that of when the principal occupation of the patient seems not to include suspected agents but is performed in contaminated environments. For instance, furnace operators in the steel, foundry, or ceramics industry, in addition to the possibility of being exposed to polycyclic aromatic hydrocarbons, can be intermittently exposed to asbestos during operations for the maintenance and renovation of furnaces, which are performed by specific professionals but can pollute the environment with asbestos.(34) Another important situation that should be addressed in history taking is the possibility that the patients have lived, for long periods of time, with family members who are exposed to carcinogens in the workplace and bring industrial dust home on their contaminated clothes.(34-37)

If necessary, pulmonologists can resort to an occupational physician or hygienist, or even visit the workplace of the patient.

Final considerations

In medical practice, making any diagnosis requires recalling that a certain disease exists. In addition, most diseases have known causes.

Tumors of occupational origin are not recognized as such in Brazil. Consequently, the affected workers are not entitled to their labor and welfare benefits. The few studies on the relationship between occupation and cancer that have been published in Brazil are restricted to academic public health(20,22) or to clinics specializing in occupational pulmonology.(25,26,35) The subject is alien to most pulmonology clinics in Brazil.

In Brazil, there are still no epidemiological records of occupational tumors that allow, in the mid- and short-term, the detection of occupational hazards and, therefore, their effective prevention. If we are "paralyzed" by the lack of scientific proof of a nexus, there is no way that we can perform primary prevention of occupational cancer. In 1965, Sir Austin Bradford Hill, known primarily for the establishing the criteria of disease causality, alerted us to the fact that scientific work is, by nature, incomplete and subject to change due to advances in knowledge. However, that does not give us the right to postpone preventive measures that ignore or reject current knowledge.(38)

11. World Health Organization. International Agency for Research on Cancer. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans: Vol.23. Lyon: International Agency for Research on Cancer; 1980.

12. International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Lyon: IARC; 2006.

13. International Agency for Research on Cancer [homepage on the Internet]. Lyon: IARC [cited 2010 May 4]. Agents Classified by the IARC Monographs, Volumes 1-100. Available from: http://monographs.iarc.fr/ENG/Classification/index.php

14. International Agency for Research on Cancer [homepage on the Internet]. Lyon: IARC [cited 2010 May 4]. Monographs available in PDF format. Available from: http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php